Toshihiko Suenaga

Reappraisal of Aquaporin-4 Astrocytopathy in Asian Neuromyelitis Optica and Multiple Sclerosis Patients

Selective aquaporin‐4 (AQP4) loss and vasculocentric complement and immunoglobulin deposition are characteristic of neuromyelitis optica (NMO). We recently reported extensive AQP4 loss in demyelinated and myelinated layers of Balós lesions without perivascular immunoglobulin and complement deposition. We aimed to reappraise AQP4 expression patterns in NMO and multiple sclerosis (MS). We evaluated AQP4 expression relative to glial fibrillary acidic protein, extent of demyelination, lesion staging (CD68 staining for macrophages), and perivascular deposition of complement and immunoglobulin in 11 cases with NMO and NMO spectrum disorders (NMOSD), five with MS and 30 with other neurological diseases. The lesions were classified as actively demyelinating (nu2003=u200366), chronic active (nu2003=u200386), chronic inactive (nu2003=u200348) and unclassified (nu2003=u200312). Six NMO/NMOSD and two MS cases showed preferential AQP4 loss beyond the demyelinated areas, irrespective of lesion staging. Five NMO and three MS cases showed AQP4 preservation even in actively demyelinating lesions, despite grave tissue destruction. Vasculocentric deposition of complement and immunoglobulin was detected only in NMO/NMOSD patients, with less than 30% of actively demyelinating lesions showing AQP4 loss. Our present and previous findings suggest that antibody‐independent AQP4 loss can occur in heterogeneous demyelinating conditions, including NMO, Balós disease and MS.

Large neurons in the tuberomammillary nucleus in patients with Parkinson's disease and multiple system atrophy

To investigate whether the histaminergic neurons degenerate in Parkinsons disease (PD) and multiple system atrophy (MSA), we studied the number of large-sized neurons in the tuberomammillary nucleus in patients with PD, patients with MSA, and age-matched controls. The number of large-sized neurons in the tuberomammillary nucleus in PD patients was not altered compared with controls, and Lewy bodies were rarely present in the tuberomammillary nucleus. In contrast, the number of large-sized neurons in the tuberomammillary nucleus in MSA patients was significantly decreased compared with controls. Thus, the central histaminergic neurons are affected in MSA and preserved in PD. NEUROLOGY 1996;46: 1693-1696

Connexin 43 astrocytopathy linked to rapidly progressive multiple sclerosis and neuromyelitis optica.

Background Multiple sclerosis (MS) and neuromyelitis optica (NMO) occasionally have an extremely aggressive and debilitating disease course; however, its molecular basis is unknown. This study aimed to determine a relationship between connexin (Cx) pathology and disease aggressiveness in Asian patients with MS and NMO. Methods/Principal Findings Samples included 11 autopsied cases with NMO and NMO spectrum disorder (NMOSD), six with MS, and 20 with other neurological diseases (OND). Methods of analysis included immunohistochemical expression of astrocytic Cx43/Cx30, oligodendrocytic Cx47/Cx32 relative to AQP4 and other astrocytic and oligodendrocytic proteins, extent of demyelination, the vasculocentric deposition of complement and immunoglobulin, and lesion staging by CD68 staining for macrophages. Lesions were classified as actively demyelinating (n=59), chronic active (n=58) and chronic inactive (n=23). Sera from 120 subjects including 30 MS, 30 NMO, 40 OND and 20 healthy controls were examined for anti-Cx43 antibody by cell-based assay. Six NMO/NMOSD and three MS cases showed preferential loss of astrocytic Cx43 beyond the demyelinated areas in actively demyelinating and chronic active lesions, where heterotypic Cx43/Cx47 astrocyte oligodendrocyte gap junctions were extensively lost. Cx43 loss was significantly associated with a rapidly progressive disease course as six of nine cases with Cx43 loss, but none of eight cases without Cx43 loss regardless of disease phenotype, died within two years after disease onset (66.7% vs. 0%, P=0.0090). Overall, five of nine cases with Cx43 loss and none of eight cases without Cx43 loss had distal oligodendrogliopathy characterized by selective myelin associated glycoprotein loss (55.6% vs. 0.0%, P=0.0296). Loss of oligodendrocytic Cx32 and Cx47 expression was observed in most active and chronic lesions from all MS and NMO/NMOSD cases. Cx43-specific antibodies were absent in NMO/NMOSD and MS patients. Conclusions These findings suggest that autoantibody-independent astrocytic Cx43 loss may relate to disease aggressiveness and distal oligodendrogliopathy in both MS and NMO.

A case of primary progressive aphasia with abnormally ubiquitinated neurites in the cerebral cortex

Abstract We report the histopathological and immunohistochemical findings in a patient with primary progressive aphasia and abnormally ubiquitinated neurites in the cerebral cortex. Neuropathological examination showed severe neuronal loss and astrocytosis with a spongy change in the frontal cortex and neostriatum. Immunohistochemistry for ubiquitin antibody showed many immunoreactive dystrophic neurites in the superficial layer of the affected cortices and putamen. Those neurites were neither argentophilic nor stained with other antibodies against neurofilament, tau, or microtubule-associated protein-2. There were no neuropathological changes characteristic of Alzheimer’s disease, Pick’s disease, or Creutzfeldt-Jakob disease. Immunoelectron microscopy using anti-ubiquitin antibody showed inclusions in the dendrites, consisting mainly of granular and filamentous material. These pathological features, unusual in primary progressive aphasia, indicate the neuropathological heterogeneity of this disease condition.

Combination of cyclosporine A with corticosteroids is effective for the treatment of neuromyelitis optica.

Neuromyelitis optica (NMO) and associated NMO spectrum disorders (NMOSDs) are neuroinflammatory diseases that frequently result in severe neurological disabilities. The aim of this study was to explore additional treatment options for NMO/NMOSD patients who are seropositive for anti-aquaporin 4 (AQP4) antibodies. We retrospectively evaluated the efficacy of immunosuppressants for NMO/NMOSDs by reviewing the clinical records of 52 patients confirmed as seropositive for anti-AQP4 antibodies. Of the 52 patients, 26 (23 women, three men) had received at least one kind of immunosuppressant other than corticosteroids. After eliminating ineligible cases, we evaluated the following 24 treatments in 22 patients (20 women, two men) that used azathioprine (AZA) (nxa0=xa09), cyclophosphamide (nxa0=xa01), cyclosporine A (CyA) (nxa0=xa09), tacrolimus (nxa0=xa02), methotrexate (nxa0=xa01), and mizoribine (nxa0=xa02). Both AZA and CyA treatments allowed us to decrease the median dose of the coadministered prednisone without affecting the expanded disability severity scale scores. In patients with relapsing-remitting courses, the annual relapse rate decreased from 1.7 (1.2–2.7) to 0.47 (0.36–0.59) after AZA treatments (nxa0=xa06, Pxa0=xa00.028), and also showed a significant decrease from 2.7 (1.8–4.3) to 0.38 (0–0.97) after CyA treatment (nxa0=xa08, Pxa0=xa00.012). These results indicate that CyA as well as AZA may help stabilize the disease activity in NMO/NMOSD patients seropositive for anti-AQP4 antibodies. This is the first case series study demonstrating the efficacy of CyA for the treatment of NMO/NMOSDs.

Significance of the Hemorrhagic Site for Recurrent Bleeding: Prespecified Analysis in the Japan Adult Moyamoya Trial

Background and Purpose— The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. Methods— The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. Results— Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01–0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39–6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60–21.27). Conclusions— Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

Ubiquitin-related cytoskeletal abnormality in frontotemporal dementia: immunohistochemical and immunoelectron microscope studies

Abstract Although reports of dementia lacking the distinctive non-Alzheimer-type histopathology have been increasing, the concept is still far from clear. It has become apparent that this population shows neuropathological heterogeneity, and some recent reports have proposed a classification or criteria for these disease conditions. Of the reported cases, frontotemporal dementia (FTD) of motor neuron disease is unique in that the neurons of the hippocampus and entorhinal cortex have ubiquitin-related abnormalities. Recently, a new ubiquitin-related abnormality, characterized by ubiquitinated inclusions in the neurites, has been found in some FTD cases. Using immunoelectron microscopy with immunogold particles, we have found that in these two disease conditions ubiquitinated inclusions consist of abnormal filaments of 10–15u2002nm in diameter. Our results support the speculation that there is a close relationship between ubiquitin and abnormal filaments in these two types of FTD, indicating that cytoskeletal-related disorders may underlie certain types of FTD.

MRI of the cervical nerve roots in the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy: a single-institution, retrospective case–control study

Objective To systematically evaluate the usefulness of assessing the cervical nerve roots by MRI for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Design Single-institution, retrospective case–control study. Setting A regional referral hospital. Participants We retrospectively enrolled 15 consecutive patients with CIDP who satisfied the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) typical and definite criteria and underwent cervical MRI. 30 control patients who had also undergone cervical MRI were included, matched with regard to sex, age and MRI system. The diagnoses of the control patients included cervical spondylosis (n=19), cervical spine trauma (n=2), infection (n=1), malignancies (n=4), demyelinating disorders (n=2) and neurodegenerative disorders (n=2). Measurement A radiologist determined the C5–C8 root diameters on the coronal short tau inversion recovery (STIR) images. Signal intensities of these roots were quantified as nerve-to-muscle contrast-to-noise ratios (CNRs), which were calculated using mean signal intensities of the roots and sternocleidomastoid muscle as well as SD of background noise. Statistical analyses were performed to determine the diagnostic accuracy of the diameters and nerve-to-muscle CNRs. Another radiologist reviewed MRI for ensuring reproducibility. Results The root diameters showed no significant differences between the patients with CIDP and control patients. The nerve-to-muscle CNRs were significantly higher in the patients with CIDP. We defined the sum of nerve-to-muscle CNRs of C5–C8 roots as the CNR score to serve as an index of overall signal intensity. The area under the receiver operating characteristic curve of CNR scores was 0.731. The reproducibility of the assessment procedure was satisfactory. Conclusions Our results suggest that assessment of the cervical nerve roots by MRI is useful for CIDP diagnosis when the signal intensities, rather than the diameters, are paid more attention on STIR images.

Small Artery Dementia in Japan: Radiological Differences between CADASIL, Leukoaraiosis and Binswanger’s Disease

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary small artery disease which is phenotypically similar to Binswanger’s disease (BD), a nonhereditary form of small artery disease. Recent studies have indicated that lesions in the temporopolar, medial frontopolar areas and external capsule are frequently seen in Caucasian patients with CADASIL. However, it remains unclear whether magnetic resonance (MR) imaging findings are helpful in diagnosing small artery disease outside countries with Caucasian populations, since CADASIL is rare despite the high prevalence of small artery disease in Japan. We examined 58 patients with small artery disease, all of whom were devoid of major vessel occlusion or severe stenosis. These patients included 7 patients from 3 families with CADASIL, 27 nondemented patients with extensive leukoaraiosis (LA) and 24 patients with BD. On T2-weighted MR images, hyperintensities in the temporopolar areas were observed in all 7 patients with CADASIL, whereas these lesions were observed in only 1 subject from each of the nondemented LA and BD groups. Hyperintensities in the medial frontopolar areas were seen in 4 of the 7 patients with CADASIL (57%) and in 14 of the 24 patients with BD (58%), and were more frequent than in the nondemented LA group (4 of the 27 patients; 15%). In contrast, hyperintensities in the external capsule were frequently observed in all groups. Therefore, temporopolar lesions can also serve as diagnostic markers for CADASIL in non-Caucasian patients.

Transient eye and nose pain as an initial symptom of pontine infarction

Headache is relatively common in Wallenberg’s lateral medullary syndrome.1,2⇓ For head pain associated with this syndrome, C.M. Fisher proposed two distinct components1: pain in the occipital, occipitofrontal, and nuchal areas attributed to ischemia of a vertebral artery and pain in the eye, nose, and cheek to ischemia in the nucleus of the descending root of the trigeminal nerve. Pontine infarction has rarely been reported to cause facial pain similar to that in Wallenberg’s syndrome.3-5⇓⇓ We report three patients with transient eye and nose pain ipsilateral to the pontine infarct.nn### Case 1.nnA 42-year-old man suddenly developed sharp facial pain radiating from the right medial side of his eye to the nose while walking. The pain lasted for several minutes. He also had a peculiar feeling similar to epistaxis on the right side. Approximately 5 minutes later, he developed left-sided numbness …